title: Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors.
abstract: In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, 51), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 μM). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 μM and 16% inhibition at 10 μM, respectively). The FAAH selectivity of the compound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected S-enantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Jayendra Z
authors.initials: JZ
authors.lastname: Patel
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Saario
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cipriano
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Igor O
authors.initials: IO
authors.lastname: Koshevoy
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases